Hemodynamic Profile of the TAH under Normal Operating Conditions
Typical hemodynamic profiles obtained with the TAH operating under normal drive conditions, with the DMCS set to normotensive patient conditions, are shown in Figure 3. The figure depicts 5 seconds of data (about eight cardiac cycles), whereas the TAH was operating at 100 BPM with a left drive pressure of 180 mm Hg. Spikes seen in the AoP waveform (Figure 3F) are due to a “bounce” or oscillatory movement of the mitral valve as it opens. The remaining channels depict pressures and flows fluctuating rhythmically with ventricular ejection. Bouncing of the mitral valve is similarly seen in the left ventricular pressure waveform as well, as a sharp spike after the pressure increase from systole. RAP (Figure 3A) varied between approximately 6 and 8 mm Hg under normal conditions. The LAP (Figure 3B) varied between approximately -10 and 45 mm Hg with an average value of about 9 mm Hg, with a spike in pressure at the beginning of systole. This spike from 0 to 45 mm Hg is similarly because of a bounce with the closure of the mitral valve. The right ventricular pressure waveform (Figure 3C) also has noisy regions at the opening of the pulmonary valve during ejection and with the closure of the valve. This is likely because of the valves oscillating for brief intervals of time, which is normal and can be seen during function. The left ventricular pressure (Figure 3D) varied between -32 and 124 mm Hg, with a mean value of 85 mm Hg. Waveforms demonstrated a clear increase in pressure with mitral valve closure and the initiation of systole. After peak systolic left ventricular pressure was reached, pressure was noted to fall but then rose quickly before becoming slightly negative (also seen clearly in the PV loops in Figures 5 and 8). These quick changes in pressure are from the vacuum engagement of the driver, to speed the mobilization of the diaphragm for rapid ventricular filling and the bouncing of the mitral valve as it opens. The AoP waveform has obvious spikes with closure of the aortic valve; this flapping of the valve is noted to be normal and can be visibly seen during normal operation. Right ventricular outflow and left ventricular inflow and outflow waveforms (Figure 3) appear as expected with the TAH set at 50% systole. The negative flow, seen in the right ventricular outflow and left ventricular inflow waveforms, occurred briefly with valve closure, with fluid moving into the closed valve, resulting in a brief period of time when the flow meters register a negative flow.
Effect of Varying Afterload on TAH Performance and DMCS Hemodynamics
Afterload in the DMCS was increased by manipulating the bellows-operated valve to restrict flow between the AoP chamber and RAP chamber. Figure 4A–C shows mean LAP, left ventricular pressure, and left ventricular outflow over a 10 second acquisition period with varying mean AoPs. As mean AoP increased, there was a small increase in average LAP (Figure 4A) and a noticeable trend in the left ventricular pressure in relation to changes in AoP. As afterload was increased, mean ventricular pressure also increased (Figure 4B). There is no notable variation in left ventricular output, Figure 4C, despite changes in afterload. Figure 5A displays PV loops at three different afterload settings providing mean AoPs of 85, 115, and 135 mm Hg. Between the three loops, there is an increase in ventricular pressure during systole, without large, noticeable differences in stroke volume. This shows that stroke work (area of the PV loop, stroke volume multiplied by pressure) increased with afterload, but cardiac output did not change, despite variations in afterload. The spikes seen on the left end of the loop are a result of mitral valve opening as filling begins. Figure 5B, adapted from Burkhoff et. al.21, shows the PV loop changes seen in a healthy human heart with increases in afterload. As afterload is increased, the stroke volume decreased and ventricular pressure during systole increased. In contrast, the TAH variations in stroke volume are not seen with increases in afterload, so that cardiac output is not compromised. This relation was noted to hold true over the range of afterloads tested. Waveforms from RAP, left ventricular pressure, AoP, and LAP during afterload variations can be seen in Figure 2, Supplemental Digital Content 2, http://links.lww.com/ASAIO/A59.
Effect of Varying Preload on TAH Performance and DMCS Hemodynamics
Preload was altered through adjustments in the right ventricle’s vacuum. The vacuum was varied between 0 and -20 mm Hg (normal is -10 mm Hg), causing EDVs of the left ventricle to vary between 21 and 54 ml. Figure 6A–D displays mean values for LAP, left ventricular pressure, AoP, and left ventricular outflow over a 10 second acquisition period are displayed. LAP (Figure 6A), ventricular pressure (Figure 6B), AoP (Figure 6C), and left ventricular outflow (Figure 6D) averages all increased with increases in preload (EDV). Waveforms from RAP, left ventricular pressure, AoP, and LAP during preload manipulations are shown in Figure 3, Supplemental Digital Content 3, http://links.lww.com/ASAIO/A60).
The preload/output relationship is shown in the Frank–Starling-like curve displayed in Figure 7A. This curve was created by comparing the EDV with the left ventricular output as preload was adjusted. Figure 7B shows the Frank–Starling Curve in a normal human heart. The curve created with the TAH demonstrates increased output with increasing preload, similar to that observed with the human heart. However, the shapes of the two curves differ, as the TAH is inelastic. There is a linear relation between fill volume and output in the TAH, whereas the curve in a human heart is more logarithmic. The PV relations created with preload variations are demonstrated in the PV loops shown in Figure 8A. Pressure spikes at the left of the loop are a result of mitral valve opening. As displayed with the average value plots (Figure 6A–D), increases in stroke volume with increased EDV are seen. Higher left ventricular pressures are observed during systole and diastole when comparing the loops. Figure 8B, adapted from Burkhoff et. al21, shows the reaction of a normal human heart to variations in preload. As in the TAH, the human heart has increased stroke volume and increased ventricular pressure during systole with increases in EDV.
This study is the first to characterize the TAH using PV relations and describe TAH function with varying preloads and afterloads on a beat-to-beat basis. Our findings verify the inelastic property of the TAH ventricle and the lack of time-varying elastance. We also demonstrate that the TAH operating under normal conditions is afterload insensitive up to the tested parameters, but is preload sensitive, demonstrating Frank-Starling-like behavior within a range of filling volumes. End-systolic and end-diastolic PV relations seen in the human heart were not observed in the TAH as the housing of the ventricle is effectively rigid in comparison to the elastance of the human ventricle. Suga and Sagawa8 demonstrated that the nonejecting canine ventricle displayed a PV relation demonstrating elastance of the ventricular wall. As volume was added to the nonejecting ventricle, increased end-systolic pressure was also seen, i.e., a direct relationship. As shown in the nonejecting TAH ventricle, Figure 2, this relationship does not hold true for the polymeric TAH. Thus, the TAH does not display the time-varying elastance characteristics of the human heart.
Overall, we see expected pressure and flow waveforms from the TAH operating with normal drive conditions under a normotensive patient load on the mock circulatory loop. We note that there are rapid fluctuations of pressures, yielding a noisy signal, because of closing and oscillations of the contained mechanical valves.
PV Relations with Variation in Afterload and Preload
When afterload was varied, the most noticeable change occurred in the average left ventricular pressure, as the ventricle must reach a higher inner pressure for the aortic valve to open. Limited variation in cardiac output is expected as the TAH is operating in full ejection conditions. The diaphragm reaches its full upright position, ejecting all volume that enters the ventricle for that cardiac cycle as the afterload or AoP stays under 180 mm Hg (the operating drive pressure). In a normal human heart, decreased cardiac output is seen with increased afterload, assuming there is no change in heart contractility. In contrast, the TAH does not demonstrate a significant change in left ventricular output with increased afterload, within our tested range. This is a result of the fact that the pneumatic driver exerts a pulse pressure able to overcome variations in afterload. These data reveal the difference in the behavior of the TAH in terms of ESPVRs compared with the human heart. No linear, ESPVR regression could be created, as the TAH does not maintain the same end-systolic PV point as the load changes, i.e., the effective slope is infinite, with no elastance (Ees) line revealed from the TAH PV loops in Figure 5A.
In a PV loop, the phases of a cardiac cycle are displayed through plotting instantaneous pressure versus volume. Loops repeat with every cardiac cycle and display how the ventricle transitions from its end-diastolic state to the end-systolic state and back. In situations of increased afterload in the TAH, the width of each loop (loop width represents stroke volume) remains constant throughout the afterload variation, with increased ventricular pressure during systole. Thus, additional stroke work (area of the PV loop) is required per cardiac cycle, because the TAH is pumping against a higher load, without a substantial change in ventricular output. In contrast, in the human heart the width (stroke volume) of the PV loop is decreased with increases in afterload.
As preload is increased in the TAH, there is a clear increase in stroke volume and end-systolic volume is similar despite variations in preload (as a result of full ejection). From a PV relation standpoint, we can create an end-diastolic PV relation (EDPVR) curve using the six different tested preloads. However, it is difficult to relate the typical EDPVR curves to the curve generated by the TAH as the TAH is behaving effectively as a rigid body, whereas an animal or human tissue ventricle has elastance. When a tissue ventricle is filled, the ventricular volume increases initially through passive filling and occupying of existing cavity space, but also via tissue stretch to further accommodate additional blood volume. In contrast, no stretching occurs within the TAH, as the housing is a nonyielding polymer and while the inner pumping diaphragm of the TAH is flexible, its positioning within the ventricle does not allow any increase in cavity volume. When the diaphragm is fully retracted, allowing the ventricle to fill, its excursion is limited by the bottom wall of the housing, which keeps it from expanding. Thus, the EDPVR’s slope in this case is only based on the fluid pressure lying above the Millar port and not from elasticity of the ventricular wall.
In the human heart, the Frank–Starling Law dictates that with increased preload, cardiac output will be increased partially from a larger contraction force, resulting from loading of the ventricular muscular wall. In the case of the TAH, increased cardiac output occurs with increased preload. However, this is not from an increase in contractility, as the drive pressure remains constant during normal function. With additional venous return, resulting in a rise in EDV, the TAH’s ventricle accommodates the additional volume, which is fully ejected. This mechanism is Frank–Starling-like and the trend is relatively linear, as the TAH is rigid, until the ventricle is fully filled. Once the ventricle is fully filled, additional volume cannot enter the ventricle and cardiac output will plateau even with increased preload as the maximum stroke volume of the TAH is 70 ml. The stroke volume limit, or high end on the Starling-like curve, will affect patient mobility or comfort specifically if the patient attempts high intensity activity.22 However, during normal activity, the Starling-like ability of the TAH allows the device to respond to increased venous return just as a healthy heart would, increasing output relative to the preload delivered. On the low end, the TAH has a residual volume of about 30 ml. If EDV is ever under 30 ml, ejection will not occur. “Partial fill, full eject” only applies to the filled volume during a cardiac cycle; the filled volume is always fully ejected, but the residual volume will remain in the ventricle. As with the EDPVR, a typical ESPVR curve cannot be generated for the TAH, as the walls of the ventricle do not contract (see Figure 4, Supplemental Digital Content 4, http://links.lww.com/ASAIO/A61). For the TAH, contraction occurs as a result of diaphragm displacement.
Limitations of the Study
To fully explore the full operating envelope of the TAH, a wider range of preloads and afterloads needs to be tested. These studies are planned for the future. We assume that the Starling-like mechanisms are limited by the high, fully filled volume of the ventricle and the low, residual volume of the ventricle. However, we were unable to reach these EDVs using the parameters varied in this testing. In the case of varied afterloads, we assume that the TAH is insensitive to variations up to the maximum drive pressure of the driver. However, we were unable to verify this assumption with test parameters as with the DMCS, as we were limited in that we could not raise the AoP higher than 135 mm Hg without changing other parameters that were held constant throughout all other experiments.
We acknowledge the existence of other mock circulatory systems that may have additional features with better modeling of patient vasculature and compliance.23–25 However, the DMCS has proven to be a success in testing the TAH in the past, which was used in the FDA approval process of the TAH, and is widely distributed in medical centers that implant the device. The volume of liquid within the inflow tubing of each ventricle acts as the working atria for the test setup. Although typical left atrial volumes can vary between 25 and 77 ml in a healthy male, the inflow tubing contained a larger than typical atrial volume because of incorporation of flow meters and tubing, creating a larger preload compared with typical human anatomy.26 However, as preload is varied throughout the course of the studies performed, we were still able to see the effects of preload variation on the TAH, despite the large atrial volume on the DMCS.
This study defines the pump performance properties of the TAH in terms of PV characteristics. The TAH does not manifest or behave with time-varying elastance. Nevertheless, the TAH operates with Frank–Starling-like behavior in response to changes in preload and with insensitivity to afterload variation, over the range of pressure tested, i.e., up to a mean AoP of 135 mm Hg. Although the present TAH has a smaller operating window compared with the human heart, i.e., it cannot achieve stroke volumes higher than 70 ml, nor vary contractile strength without changing driver settings, the TAH by virtue of its defined maximum volume, set material property, and defined nonvarying elastance can operate equally well, i.e., providing cardiac output comparable with the human heart, over a wide range of loading conditions.
The characterization of the pneumatically driven SynCardia TAH that has emerged in this study may aid in the development of physiological control algorithms, next generation TAH designs, and will further our understanding of how the TAH performs in patients over a range of hemodynamic conditions. In the future, the construction of an artificial heart with expansile volume capabilities and time-varying elastance properties might extend the operating envelope of the artificial heart, bringing it closer to the maximum range of human physiological parameters.
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total artificial heart; elastance; pressure–volume relation; Donovan mock circulation; mechanical circulatory support; heart failure
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